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The Journal of Neuroscience, August 15, 2000, 20(16):6225-6231
The Role of Ventromedial Prefrontal Cortex in the Recovery of
Extinguished Fear
Gregory J.
Quirk,
Gregory K.
Russo,
Jill L.
Barron, and
Kelimer
Lebron
Department of Physiology, Ponce School of Medicine, Ponce, Puerto
Rico 00732
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ABSTRACT |
Conditioned fear responses to a tone paired with footshock
extinguish when the tone is presented repeatedly in the absence of shock. Rather than erase the tone-shock association, extinction is
thought to involve new learning accompanied by inhibition of conditioned responding. Despite much interest in extinction from a
clinical perspective, little is known about the neural circuits that
are involved. Although the prefrontal cortex has a well established role in the inhibition of inappropriate behaviors, previous reports have disagreed as to the role of the ventromedial prefrontal cortex (vmPFC) in extinction. We have reexamined the effects of electrolytic vmPFC lesions made before training on the acquisition, extinction, and
recovery of conditioned fear responses in a 2 d experiment. On Day
1 vmPFC lesions had no effect on acquisition or extinction of
conditioned freezing and suppression of bar pressing. On Day 2 sham
rats recovered only 27% of their acquired freezing, whereas vmPFC-lesioned rats recovered 86%, which was indistinguishable from a
control group that never received extinction. The high recovery in
lesioned rats could not be attributed to decreased motivation or
altered sensitivity to footshock. vmPFC lesions that spared the caudal
infralimbic (IL) nucleus had no effect. Thus, the vmPFC (particularly
the IL nucleus) is not necessary for expression of extinction, but it
is necessary for the recall of extinction learning after a long delay.
These data suggest a role of the vmPFC in consolidation of extinction
learning or the recall of contexts in which extinction took place.
Key words:
extinction; infralimbic; prelimbic; fear conditioning; amygdala; inhibition
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INTRODUCTION |
Prefrontal cortex has long been
implicated in inhibition of inappropriate responses. Lesions of medial
prefrontal cortex (mPFC) cause perseverative responding in animals and
humans and cause deficits in reversal tasks (for review, see Kolb,
1984 ; Fuster, 1997). Perseverative responding in prefrontal animals was
extended to conditioned fear when it was shown that rats with mPFC
lesions could acquire freezing responses to a tone paired with a
footshock, but they required many more days to extinguish those
responses when the tone was presented alone (Morgan et al., 1993). More recent data support the hypothesis that mPFC is involved in the inhibition of fear responses (Bremner et al., 1999; Herry et al., 1999;
Morrow et al., 1999), and it has been suggested that deficits in
extinction of conditioned fear may cause certain anxiety disorders (Charney and Deutch, 1996; Pitman, 1997).
Many questions remain, however, concerning the role of the
ventromedial prefrontal cortex (vmPFC) in extinction of fear. Following the original report by Morgan et al. (1993), Gewirtz et al. (1997) found no effect of vmPFC lesions on extinction of conditioned fear
responses. To explain this discrepancy, Gewirtz et al. (1997) suggested
that the prolonged extinction might have been attributable to increased
acquisition in the lesioned animals, which was masked by asymptotic
freezing levels. Another possible explanation for the discrepancy
between the two studies concerns the extent to which the infralimbic
nucleus (IL) was destroyed by the lesions. The IL contributes the
majority of vmPFC inputs to the central nucleus of the amygdala (Sesack
et al., 1989; Hurley et al., 1991), which plays a key role in the
expression of behavioral and autonomic indices of conditioned fear
(Kapp et al., 1979; LeDoux et al., 1988; Helmstetter, 1992; McCabe et
al., 1992; Powell, 1994; Campeau and Davis, 1995; Maren, 1999;
Amorapanth et al., 2000). IL also projects to many of the hypothalamic
and midbrain sites that mediate fear responses (Sesack et al., 1989;
Hurley et al., 1991).
We addressed these issues by comparing the effects of inclusive vmPFC
lesions with IL-sparing rostral vmPFC lesions on the acquisition and
extinction of conditioned fear responses. To maximize our chances of
detecting potentiated acquisition in the lesioned group, we used a
paradigm that produces a gradual acquisition curve with submaximal
freezing. Previous studies have examined extinction over many days,
with few extinction trials given per day. The ability of vmPFC rats to
extinguish fear responses within a single session has not been
examined. We conditioned and extinguished rats in a single day, and we
tested for recovery of fear to the tone 24 hr later. Two questions were
asked. (1) Are vmPFC-lesioned rats able to express extinction from
trial-to-trial on Day 1? (2) Are vmPFC-lesioned rats able to recall
extinction learning on Day 2? If the lesions prevented rats from
inhibiting fear responses, deficits would be expected on both Days 1 and 2. Preserved extinction on Day 1 followed by recovery of fear on
Day 2 would suggest a more complex role of vmPFC in extinction of fear.
An abstract containing some of these data has been published (Quirk et
al., 1998).
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MATERIALS AND METHODS |
Subjects. All procedures were approved by the
Institutional Animal Care and Use Committee (IACUC) of Ponce School of
Medicine, in compliance with the Guide for the Care and Use of
Laboratory Animals (Department of Health and Human Services publication
86-23). Male rats (Sprague Dawley) weighing ~300 gm were transferred
from the Ponce School of Medicine colony to the laboratory, where they were housed individually in transparent polyethylene cages located in a
negative-pressure clean room (Colorado Clean Room, Ft. Collins, CO) and
maintained on a 12 hr light/dark schedule with free access to water.
For 7 d the rats were handled daily and fed 10-15 gm/d of
standard rat chow until they reached 85% of their original body
weight. During this period they also were acclimated to the 45 mg food
pellets (Bioserve, Frenchtown, NJ) used for bar-press training.
Bar-press training. After handling, the rats were trained to
press for food in a standard conditioning chamber, 25 × 29 × 28 cm, with aluminum and Plexiglas walls (Coulbourn Instruments, Allentown, PA). The chamber included a shock floor with 0.5 cm diameter
steel bars spaced at 1.8 cm and a response lever on one wall positioned
6.5 cm from the floor. A speaker was mounted to the outside of the
opposite wall from the lever and faced a grating to permit sound to
enter the chamber. The chamber was housed in a sound-attenuating box
(Med Associates, Burlington, VT) to reduce ambient sound to 55 dB.
Pellet delivery was controlled by a computer running commercial
behavioral testing software (Coulbourn Winlinc). Initially, rats
received one pellet for each press. The reinforcement ratio was reduced
gradually until rats learned to press >20/min with a variable-interval
schedule of reinforcement (VI-60). Bar-press training lasted ~1 week,
after which rats were assigned to experimental and control groups on
the basis of the output of a pseudo-random number generator
(http://www.randomizer.com). A small number of rats failing to press
>20/min were excluded from the study.
Surgery. After pretreatment with atropine sulfate (0.27 mg/kg, i.p.), the rats were anesthetized with Nembutal (sodium
pentobarbital, 60 mg/kg, i.p.) and placed into a stereotaxic apparatus
(David Kopf Instruments, Tujunga, CA). Supplemental doses of Nembutal (5 mg) were given as needed to maintain a deep level of anesthesia, as
indicated by a slow respiratory rate and lack of response to tail
pinch. Body temperature was monitored with a rectal probe and
maintained at 37-39°C with a heated gel pad. Surgical tools were
sterilized with an antibacterial solution (Cidex) and rinsed in sterile
water. The cranium was exposed and scraped, and a cautery was used to
stop bleeding from the bone. After leveling the scalp so that lambda
and bregma were in the same horizontal plane, we drilled burr
holes bilaterally over the mPFC with a dental drill. A 125 µm
Teflon-insulated wire electrode with an 0.5 mm exposed tip (Rhodes
Medical Instruments, Tujunga, CA) was lowered into the vmPFC, targeting
the infralimbic nucleus. The coordinates relative to bregma were 2.7 mm
anterior, 0.5 mm lateral, and 5.2 mm ventral (Paxinos and Watson,
1998). An electrolytic lesion was made by passing 1.0 mA of anodal
current for 12 sec, using a DC stimulator with constant current output
(Grass-Astro Med, Warwick, RI). For sham-operated rats the electrode
was lowered to a point just above the prelimbic cortex (2.6 mm ventral
to bregma), but no current was passed. The electrodes were removed and
sterile bone wax was used to fill the burr hole. The skin was sutured
with surgical thread, and antibiotic ointment was applied to
prevent infection. Rats were given a single injection of buprenorphine
hydrochloride (Buprenex, 0.02 mg/kg, i.m.) to relieve postoperative
pain and were allowed 1 week to recover.
Fear conditioning. During recovery from surgery the rats
received an additional 1-3 d of bar-press training, after which fear conditioning commenced. The conditioned stimulus (CS) was a 4 kHz pure
tone lasting 30 sec, with a loudness of 80 dB SPL. The unconditioned
stimulus (US) was a scrambled footshock delivered to the floor bars,
with an intensity of 0.5 mA and duration of 0.5 sec (tone and shock
coterminating). The experiment took place over 3 d. On
experimental Day 0 the rats were allowed to bar press for 10 min in the
conditioning chamber. No tones or shocks were given. The next day (Day
1) the rats were given five habituation trials (tone alone). This was
followed immediately by seven conditioning trials (tones paired with
shock). After a 1 hr rest period in the home cage the rats were
returned to the conditioning chamber for 15 extinction trials (tone
alone). Day 1 training lasted ~3 hr. On Day 2 the rats received an
additional 15 extinction trials, followed by two unsignaled footshocks
(0.5 mA, 0.5 sec) and 15 more extinction trials. Day 2 lasted ~2 hr.
During all phases of the experiment the intertrial interval varied at
~4 min, and food reward was continuously available on a VI-60
schedule. A computer controlled the delivery of shocks, tones, and food
pellets. Between each session the floor trays and shock bars were
removed and cleaned with a soapy sponge, and the chamber walls were
wiped with a damp cloth.
There were four experimental groups. mPFC lesion and sham-operated rats
were treated as above. Two additional control groups received a
slightly different treatment. A "sham-unpaired" group received sham
surgery and fear conditioning as described, except that the footshock
and tone were unpaired explicitly during the conditioning phase. This
served as a control of nonassociative effects of the stimuli. An
"extinction-naïve" group received sham surgery and was
conditioned identically to the lesion and sham groups. At 1 hr after
conditioning these rats were placed in the chamber and allowed to press
for food, but no extinction tones were given. The amount of time spent
in the chamber on Day 1 was identical for sham and
extinction-naïve groups.
Conditioned fear responses to the tone were measured in two ways:
percent freezing and suppression of bar pressing. The cumulative time
spent freezing (absence of all movements except those related to
respiration) was measured with a digital stopwatch either during the
experiment or afterward from videotape. Observers measuring freezing
were blind with respect to group assignment. For the suppression
measure, bar presses were time-stamped, stored to disk, and analyzed
off-line with an Excel spreadsheet programmed for this purpose. The
rates of bar pressing during the 60 sec that preceded each tone
("pretone") were compared with the rates during the 30 sec tone
("tone"). As previously described, a suppression ratio was
calculated (Bouton and Bolles, 1980; Armony et al., 1997):
The suppression ratio takes into account changes in baseline
press rate in determining the effect of the tone on pressing. A value
of 1 indicates complete suppression of bar pressing during the tone,
whereas a value of 0 indicates no suppression whatsoever. During trials
in which both pretone and tone were 0, a value of 1 was used.
Sensitivity to footshock. After the completion of all
extinction trials, lesion and sham groups were tested for sensitivity to footshock. Rats were placed into the conditioning chamber and given
unsignaled footshocks of increasing amplitude. Starting with 0.05 mA,
footshock was increased in 0.05 mA increments until three response
thresholds were reached: noticing (an orienting head movement),
flinching (hind paws briefly raised off the bars), and vocalizing. An
observer blind with respect to experimental group assignment measured thresholds.
Histology. After Day 2 the rats were given an overdose of
Nembutal (100 mg/kg, i.p.) and perfused transcardially with
physiological saline, followed by 10% buffered formalin. Brains were
removed and post-fixed in 10% formalin with 30% sucrose.
Subsequently, brains were paraffin-embedded and sectioned at 20 µm on
a microtome. Every third section was mounted on gelatin-coated slides
and stained with cresyl violet to show Nissl bodies. Lesions were
traced onto selected drawings from a stereotaxic atlas (Paxinos and
Watson, 1998). Decisions to include or exclude animals on the basis of anatomical criteria were made without knowledge of the experimental results.
Data analysis. Freezing scores (in sec) and suppression
ratios were compared with ANOVA (STATISTICA, Statsoft , Tulsa,
OK). In most cases a two-way ANOVA with repeated measures was used. Following a significant omnibus F ratio, all post
hoc comparisons were performed by using Scheffé's method.
In all figures the data are represented as means ± SEM.
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RESULTS |
Location of lesions
Following previous studies (Morgan et al., 1993; Gewirtz et al.,
1997), we targeted the ventral part of medial prefrontal cortex
(vmPFC), which includes the ventral prelimbic cortex (PL, area 32) and
the infralimbic cortex (IL, area 25). The border between the PL and IL
is marked by the fusing of layers II and III in IL (Zilles and Wree,
1995). Previous studies have shown that damage to the dorsal mPFC (the
anterior cingulate cortex, area 24) increases fear responses during
both acquisition and extinction phases (Morgan and LeDoux, 1995). For
this reason, animals with mPFC damage dorsal to the mid-prelimbic area
(other than minor damage caused by electrode insertion) were discarded, leaving 17 rats with lesions restricted to vmPFC. Of these, 11 included
>70% destruction of IL at all levels, whereas six spared most or all
of caudal IL. These groups were compared separately and will be
referred to as vmPFC-inclusive (vmPFC-i) and vmPFC-rostral (vmPFC-r)
groups (Fig. 1). A total of 29 sham-operated rats (with no damage to dorsal mPFC other than the
electrode track) served as controls. Shams were divided into three
groups: "sham" (n = 11), "sham-unpaired"
(n = 7), and "extinction-naïve"
(n = 11). The total number of rats was 46.
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Figure 1.
A diagram showing the extent of lesions in
ventromedial prefrontal cortex (vmPFC). The largest
(outline) and smallest (filled) lesions are shown
for each level. A, The vmPFC-inclusive group showed
>70% destruction of the infralimbic nucleus at all levels
(n = 11). B, The vmPFC-rostral group
spared some or all of the IL nucleus caudally (n = 6). Cg1, Anterior cingulate cortex; DP,
dorsal peduncular nucleus; IL, infralimbic nucleus;
LS, lateral septum; MO, medial orbital
cortex; M2, secondary motor cortex; PrL,
prelimbic cortex; VO, ventral orbital cortex. Numbers
indicate location anterior to bregma (mm). Modified from Paxinos and
Watson (1998).
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Acquisition and extinction of fear responses on Day 1
Both freezing and suppression of bar pressing were used as indices
of conditioned fear. Conditioned suppression (also known as the
conditioned emotional response, CER; Estes and Skinner, 1941) offers
the important advantage of maintaining a constant level of activity
against which freezing to a discrete CS can be measured reliably. This
is particularly important during long extinction sessions (in excess of
1 hr) to prevent rats from becoming drowsy or falling asleep.
Sham and lesion groups rapidly acquired conditioned freezing and
suppression to the tone during the conditioning phase. Figure 2 shows freezing and suppression scores
for each trial of the experiment (for simplicity, only sham and vmPFC-i
groups are plotted). Conditioned responses increased gradually and did
not reach a plateau. Figure 3 summarizes
these data in blocks of trials for sham, vmPFC-i, and vmPFC-r groups.
Peak freezing levels for the three groups (measured at the beginning of
extinction) were 67, 77, and 56% of the tone, respectively. Peak
suppression ratios were 0.85, 0.95, and 0.77 for sham, vmPFC-i, and
vmPFC-r groups, respectively. One-way ANOVAs showed no significant
difference between groups during acquisition (freezing:
F(2,25) = 0.62, p > 0.05; suppression: F(2,25) = 1.82, p > 0.05). In contrast to the animals that received
paired tones and shocks, the sham-unpaired group showed virtually no
freezing to the tone throughout the entire experiment. The maximum
freezing level for sham-unpaired animals in any trial was only 9%.
Thus, the high freezing values observed in the lesion and sham groups
were not attributable to sensitization effects.
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Figure 2.
Average freezing (A) and
suppression (B) values for each trial of the
experiment. A habituation phase (tones alone) was followed by a
conditioning phase (tones plus shocks) and an extinction phase (tones
alone). Freezing is expressed as a percentage of the 30 sec tone spent
motionless. Suppression of bar pressing to the tone was expressed as a
suppression ratio, which compared pretone rates with tone rates (see
Materials and Methods). A ratio of 1.0 indicated maximal suppression to
the tone, whereas 0 indicated no suppression. No difference in fear
responses was found between the groups on Day 1. However, vmPFC-i
animals showed higher recovery of the fear responses at the beginning
of Day 2. Empty circle, Sham-operated; filled
diamond, vmPFC-i lesion. In this and all subsequent figures the
error bars indicate SEM.
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Figure 3.
Average freezing (A) and
suppression (B) values for two-trial blocks on
Day 1 and Day 2 shown for sham-operated (empty bars),
vmPFC-i (filled bars), and vmPFC-r
(hatched bars) groups. Note the high recovery of fear
responses to the tone on Day 2 in the vmPFC-i group, but not in the
vmPFC-r group. ANOVA indicated that the vmPFC-i group was significantly
different from the sham group only on Day 2 (p < 0.001).
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At 1 hr after conditioning the rats were given 15 extinction
trials. Conditioned freezing and suppression responses rapidly extinguished in the lesion groups as well as in the shams (see Figs. 2,
3). At the conclusion of the extinction session, freezing and
suppression values extinguished to preconditioning values. Two-way
ANOVAs performed on the three phases of the experiment from Day 1 (habituation, early extinction, and late extinction) showed a
significant main effect of phase (freezing:
F(2,50) = 197.1, p < 0.001; suppression: F(2,50) = 93.8, p < 0.001), but no effect of group (freezing:
F(2,25) = 1.3, p > 0.05; suppression: F(2,25) = 1.5, p > 0.05) or interaction between group and phase (freezing: F(4,50) = 1.1, p > 0.05; suppression:
F(4,50) = 0.9, p > 0.05). Thus, all three groups acquired and extinguished equivalent amounts of conditioned freezing and suppression on Day 1. Post hoc comparisons showed no significant differences between the beginning and end of Day 1 (habituation vs late extinction) in either
measure, suggesting that extinction on Day 1 was near complete.
Recovery of conditioned fear responses on Day 2
On Day 2 an additional 15 extinction trials were given to test for
spontaneous recovery of fear responses to the tone. As shown in Figure
3, sham and vmPFC-r groups displayed relatively little freezing (sham,
18%; vmPFC-r, 6%) or suppression (sham, 0.24; vmPFC-r, 0.46) to the
tone on Day 2. In contrast, the vmPFC-i animals showed pronounced
freezing (54%) and suppression (0.87) to the tone. A two-way ANOVA
across Days 1 and 2 showed a significant main effect of group
(freezing: F(2,25) = 7.7, p < 0.01; suppression: F(2,25) = 7.5, p < 0.01), and phase (freezing: F(3,75) = 138.1, p < 0.001; suppression:
F(3,75) = 69.9, p < 0.001), as well as a significant interaction between group and phase
(freezing: F(6,75) = 8.2, p < 0.001; suppression:
F(6,75) = 3.9, p < 0.001). Post hoc comparisons indicated that the experimental
groups differed only on Day 2. For freezing on Day 2, the vmPFC-i group
was significantly higher than either the sham (p < 0.001) or vmPFC-r (p < 0.001) groups. For
suppression, the vmPFC-i group was significantly higher than shams
(p < 0.001), but not vmPFC-r rats
(p > 0.05). In both measures the vmPFC-i
group's responses on Day 2 were not significantly different from the
peak values acquired on Day 1, suggesting a high level of recovery in
the vmPFC-i group.
The percentage of recovery of conditioned fear was calculated by
dividing the freezing at the beginning of Day 2 (trials 1-2) by the
conditioning phase on Day 1 (trials 6-7). Figure
4 shows the percentage of recovery for
four groups: vmPFC-i, vmPFC-r, sham, and extinction-naïve.
Extinction-naïve rats were sham-operated and conditioned, but
they were not exposed to extinction tones on Day 1. As expected,
extinction-naive rats recovered most of their acquired freezing to the
tone (89%) on Day 2. In contrast, shams that were extinguished on Day
1 recovered only 27% of acquired freezing. vmPFC-i rats resembled
extinction-naive controls, recovering 86%, whereas vmPFC-r rats
resembled shams, recovering only 20%. Comparison of recovery with a
one-way ANOVA indicated a highly significant effect of group
(F(3,35) = 11.5, p < 0.001). Post hoc tests confirmed the visual impressions of
Figure 4A. vmPFC-i rats were significantly higher
than shams (p < 0.01) and vmPFC-r (p < 0.01) rats, but not significantly
different from the extinction-naive group (p > 0.05). The suppression values also showed a significant main effect of
group (F(3,35) = 6.0, p < 0.001). vmPFC-i rats recovered significantly more
suppression than shams (p < 0.05) but were not
significantly higher than vmPFC-r rats (p > 0.05). The high recovery of fear responses in vmPFC-i rats was not
attributable to any residual fear from the end of Day 1, because the
difference between sham and vmPFC-i groups at the end of Day 1 was not
significant (see above).
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Figure 4.
Recovery of extinguished freezing
(A) and suppression (B)
responses on Day 2, expressed as a percentage of fear response acquired
on Day 1. Four groups are shown: extinction-naïve,
sham-operated, vmPFC-i (PFC-i), and vmPFC-r
(PFC-r). An asterisk indicates that the
vmPFC-i group was significantly higher than the sham group
(p < 0.001), but not significantly
different from the extinction-naïve group
(p > 0.05).
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Rate of extinction on Day 2
There are two possible explanations for the high recovery of
extinguished fear responses in vmPFC-i animals. (1) The extinction learning from Day 1 was never consolidated and therefore lost entirely,
or (2) the extinction learning from Day 1 was consolidated but was
inaccessible at the beginning of Day 2. One way of testing whether a
memory is present but is not being expressed is to do a savings test. A
comparison of extinction curves for Days 1 and 2 (see Fig. 2) shows
that vmPFC-i rats extinguished more quickly on Day 2, suggesting
savings. However, the extinction session on Day 2 occurred 24 hr after
conditioning, whereas the extinction session on Day 1 occurred only 1 hr after conditioning. This difference could account for the lower fear
observed on Day 2. We controlled for elapsed time after conditioning by
comparing the extinction rate of vmPFC-i animals on Day 2 with the
extinction-naïve group, also on Day 2. We reasoned that, if
vmPFC-i rats were able to recall extinction, they should extinguish
faster than rats that were being extinguished for the first time.
Figure 5 shows that vmPFC-i rats in fact
did extinguish more rapidly than extinction-naïve controls for
both freezing and suppression. Thus, although lesioned rats showed full
recovery of fear responses on Day 2, they retained some component of
extinction training, as indicated by the rapid rate of extinction.
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Figure 5.
Extinction trials on Day 2 for vmPFC-i and
extinction-naive groups, shown for freezing (A)
and suppression (B). Despite complete recovery of
fear responses on Day 2, vmPFC-i rats showed savings in their rate of
extinction, suggesting some retention of extinction learning from Day
1.
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Reinstatement of extinguished fear responses
After 15 extinction trials on Day 2, the rats received two
unsignaled shocks, followed (8 min later) by an additional 15 extinction trials. Previous studies have shown that unsignaled shocks
can reinstate extinguished conditioned responses (Rescorla and Heth, 1975). The unsignaled shocks caused a moderate increase in freezing to
the tone in sham (30%), vmPFC-i (40%), and vmPFC-r (27%) groups, which rapidly extinguished. These data are shown in Figure
6A. A two-way ANOVA
comparing preshock and postshock (trials 15-16) freezing values showed
a main effect of trial (F(1, 25) = 39.4, p < 0.001) but no effect of group
(F(2,25) = 0.6, p > 0.05), suggesting that the shocks increased all groups equivalently. To
determine whether freezing was tone-specific or simply a continuation
of pretone freezing, we subtracted pretone freezing from tone freezing in sham and sham-unpaired groups. This had little effect on sham freezing values, dropping them from 30 to 25% sec in trial 16. In
contrast, unpaired rats dropped from 18 to  0.4% sec (Fig. 6B). An ANOVA on the difference values indicated a
significant main effect of group (F(1,
13) = 6.2, p < 0.05), a trend for main effect of trial (F(1, 13) = 4.4, p = 0.055), and a significant interaction between trial
and group (F(1, 13) =6.0,
p < 0.05). Thus, the tone-induced freezing observed in
sham-paired and vmPFC lesion groups that follows unsignaled shocks
appears to be attributable to reinstatement of a previously conditioned
association rather than a sensitization effect, because sham-unpaired
rats showed no increase. Lesioning vmPFC did not interfere with this
reinstatement process.
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Figure 6.
Reinstatement of freezing to the tone.
A, Sham, vmPFC-i, and vmPFC-r groups increased their
freezing to the tone after two unsignaled shocks. B,
Freezing in the pretone period was subtracted from freezing during the
tone for sham and sham-unpaired groups. Shams showed significant
tone-induced freezing that was greater than pretone freezing, but
sham-unpaired did not, indicating that increased freezing was not
attributable to a sensitization effect.
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Footshock sensitivity and activity controls
Despite the large effect of vmPFC-i lesions on the recovery of
fear responses on Day 2, there was no effect of the lesions on
spontaneous press rates. Figure
7A shows the average pretone press rates for sham and vmPFC-i groups on Days 1 and 2. Shams and
lesioned rats pressed at ~20/min throughout. There were no significant differences between groups or between blocks of trials. In
other words, pretone press rates were constant during periods when fear
to the tone changed dramatically. Two conclusions can be drawn. First,
lesions of vmPFC-i did not produce a general deficit in bar pressing
nor a reduction in motivation to press for food. Second, pretone press
rates revealed no evidence of context conditioning in either group. For
example, at the beginning of extinction on Day 1, when pressing during
the tone was most suppressed in both groups, pretone rates were
unchanged.
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Figure 7.
Pretone press rates and footshock sensitivity.
A, Spontaneous press rates during the 60 sec before tone
onset for sham and vmPFC-i groups. Blocks of five trials during the
extinction sessions of Day 1 and Day 2 are shown. Press rates did not
differ between groups or across trials. B,
Footshock response thresholds for sham and vmPFC-i groups. vmPFC-i
lesions did not alter sensitivity to footshock.
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At the conclusion of the experiment, sham and vmPFC-i groups were
tested for footshock response thresholds. Three behaviors were
assessed: notice, flinch, and vocalize (Fig. 7B). A two-way ANOVA showed a significant main effect of behavioral response (F(2, 28) = 66, p < 0.0001), but no effect of group (F(2,
28) = 0.58, p > 0.05). Thus, the increased
recovery of fear in vmPFC-i rats cannot be attributed to an increase in
sensitivity to footshock because vmPFC-i lesions did not alter response
thresholds significantly.
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DISCUSSION |
We have examined the effects of electrolytic lesions of vmPFC on
the acquisition, extinction, and recovery of conditioned fear,
following earlier conflicting reports (Morgan et al., 1993; Gewirtz et
al., 1997). Animals without vmPFC acquired normal levels of freezing
and suppression in response to a tone that was paired with footshock.
Furthermore, vmPFC-lesioned animals extinguished their fear responses
to the tone when it was presented without the shock, in an extinction
session. However, 24 hr later the rats with vmPFC lesions that included
most of the infralimbic nucleus (vmPFC-i) recovered most of the
acquired freezing and suppression. In contrast, sham-operated rats
recovered little conditioned fear. Rats with lesions of vmPFC that
spared IL (vmPFC-r) were similar to shams. Finally, both lesion groups
showed normal reinstatement of extinguished fear to the tone that
followed unsignaled shocks.
Gewirtz and colleagues (1997) attempted to explain the discrepancy
between their negative findings and those of Morgan et al. (1993) by
suggesting that vmPFC lesions increased acquisition, thereby prolonging
extinction. In fact, lesions of the dorsal mPFC have just
this effect (Morgan and LeDoux, 1995). Increased acquisition of
freezing in vmPFC-lesioned rats was not reported by Morgan et al.
(1993), but it could have been missed because of the asymptotic
freezing levels in that study. This is not a problem in the present
study because we used a paradigm that (1) produced a gradual
acquisition curve in which potentiated acquisition could be detected
and (2) produced submaximal freezing. Under these conditions the
vmPFC-lesioned rats did not acquire significantly more conditioned
freezing than controls did. We therefore believe it is unlikely that
extinction-related deficits in vmPFC rats are attributable to increased
levels of acquisition. Although acquisition appeared normal in lesioned
rats, we cannot rule out the possibility that animals without vmPFC
acquire CS-US associations in a manner different from intact animals.
Preserved acquisition of conditioned fear in animals with damage
to vmPFC agrees with previous findings for conditioned freezing (Morgan
et al., 1993; Morrow et al., 1999), blood pressure changes (Fryztak and
Neafsey, 1994), eyeblink responses (Buchanan and Powell, 1982; Chachich
and Powell, 1998), and skin conductance changes (Bechara et al., 1999).
Powell and colleagues have shown that mPFC lesions block heart rate
conditioning in rabbits (Buchanan and Powell, 1982; Powell,
1994), but ventral mPFC lesions similar to ours had no effect
(Powell et al., 1994).
We observed that vmPFC animals exhibited normal extinction of
conditioned fear responses during the extinction session on Day 1. Thus, the expression of extinction, which depends on GABAergic systems
(Harris and Westbrook, 1998), is normal in vmPFC-lesioned rats. This
argues against the simple hypothesis that mPFC is the structure
responsible for inhibiting fear responses during an extinction session.
A recent study confirms that vmPFC damage does not prevent
within-session extinction of conditioned skin conductance responses in
humans (Bechara et al., 1999). These findings suggest that vmPFC does
not perform a working memory function during extinction, because
retention of nonreinforcement is normal from trial to trial. A
different conclusion was reached by Morrow and colleagues, who recently
demonstrated that 6-hydroxydopamine (6-OHDA) lesions of vmPFC prevented
within-session extinction of conditioned freezing (Morrow et al.,
1999). This effect was dependent on footshock intensity and was
observed with 0.8 mA, but not 0.4 mA (a value closer to the present
study). The recruitment of catecholamine systems during stress (Bremner
et al., 1996) may play a greater role in extremely aversive rather than
mildly aversive associations. Interestingly, locus coeruleus lesions that depleted frontal cortex of norepinephrine interfered with extinction between sessions, but not within a session, in a conditioned eyeblink paradigm (McCormick and Thompson, 1982).
Despite full extinction of conditioned fear responses on Day 1, vmPFC-i-lesioned rats recovered the same amount of freezing on Day 2 as
extinction-naïve rats. The difference between vmPFC-i and sham
groups cannot be attributed to food deprivation or the use of the CER.
Lesioned rats were motivated equally to press for food, as indicated by
similar pretone press rates in vmPFC-i and sham rats. Food deprivation
by itself does not affect conditioned freezing (Maren and Fanselow,
1998). The recovery of extinguished fear we observed could slow
extinction rates in animals tested over many days (Morgan et al.,
1993). Thus, vmPFC may be required for consolidation of extinction
learning such that damage to vmPFC would prevent long-term, but not
short-term, memory for extinction.
An alternative possibility concerns the role of context. Although
conditioned fear associations to a tone CS are in large part
independent of context, extinction is context-dependent. Accordingly,
extinguished fear responses are "renewed" when rats are placed in a
chamber different from the one in which extinction occurred (Bouton and
King, 1983). It has been proposed that context determines the meaning
of a conditioned stimulus that has been made ambiguous by an extinction
experience (Bouton, 1994). This suggests that the CS is linked to the
context during extinction (Harris et al., 2000). The recovery of
extinguished fear responses we observed is similar to the renewal
phenomenon and suggests that vmPFC may be necessary for recalling a
context in which extinction occurred.
It is difficult with the present data to distinguish between
consolidation and contextual functions for vmPFC in extinction. We
observed normal reinstatement of extinguished fear with unsignaled shocks, which is also context-dependent (Bouton and King, 1983). In
their original report Morgan et al. (1993) found no effect of vmPFC
lesions on extinction of contextual freezing. However, the savings we
observed on Day 2 suggest that consolidation of extinction did occur to
some extent in lesioned rats. Additional experiments are needed to
determine whether varying temporal or contextual parameters could
induce lesioned rats to recall extinction learning on Day 2. In
addition, multichannel recordings from vmPFC neurons, similar to
previous analyses of amygdala and auditory cortex (Quirk et al., 1995,
1997), are currently underway that will determine the features of
extinction training signaled by vmPFC neurons.
Our findings suggest a high degree of anatomical specificity in the
control of spontaneous recovery by prefrontal cortex. Although complete
lesions of vmPFC (prelimbic and infralimbic cortices) caused recovery
of fear, lesions that spared the caudal IL had no effect. This could
account for the negative findings of Gewirtz and colleagues, who spared
the caudal IL in a proportion of their animals [Gewirtz et al. (1997),
their Fig. 1]. Whereas the mPFC projects to both the basolateral and
central nuclei of the amygdala (McDonald, 1998), projections to the
central nucleus (Ce) arise exclusively from IL (Hurley et al., 1991;
Takagishi and Chiba, 1991; Buchanan et al., 1994). In fact, IL
projections to Ce are strongest from its caudal part (Room et al.,
1985; McDonald et al., 1996). The central nucleus of the amygdala
mediates conditioned freezing, autonomic changes, and potentiated
startle via its projections to periaqueductal gray (PAG), lateral
hypothalamus, and caudal pontine reticular formation, respectively
(Davis, 1994; Fendt and Fanselow, 1999; LeDoux, 2000). IL
projections to Ce could influence all of these conditioned responses to
extinguished stimuli. Alternatively, direct projections from the IL to
the PAG and hypothalamus (Hurley et al., 1991; Takagishi and Chiba,
1991) might modulate fear responses independently of the amygdala.
Although both circuits are plausible, the amygdala seems to play a key
role because blockade of NMDA receptors in the amygdala prevents
extinction (Falls et al., 1992). Also, whereas lesions of Ce prevent
the acquisition of both conditioned suppression (Thompson and
Schwartzbaum, 1964; Killcross et al., 1997) and conditioned freezing,
recent data suggest that lesions of PAG block freezing but leave
conditioned suppression intact (Amorapanth et al., 1999). We observed
effects of vmPFC lesions on both behaviors, consistent with vmPFC
modulation of a structure upstream from PAG, such as Ce.
In conclusion, we have shown that rats with lesions of ventral mPFC are
able to acquire and extinguish conditioned fear, but they recover
extinguished fear when tested 24 hr later. These findings extend
previous studies (Morgan et al., 1993; Herry et al., 1999; Morrow et
al., 1999) by showing that vmPFC is necessary for recalling a
previously learned extinction experience, rather than learning
extinction per se. Recovery of extinguished fear is a common feature of
anxiety disorders such as post-traumatic stress disorder (PTSD). Recent
functional imaging studies have shown abnormally low activity in the
ventromedial prefrontal cortex of PTSD patients who are reexposed to
trigger stimuli (Shin et al., 1997; Bremner et al., 1999). Further
study of the vmPFC and its targets in the amygdala and elsewhere may
hold the key to understanding how the brain keeps conditioned fear
associations in check.
| |
FOOTNOTES |
Received March 16, 2000; revised May 19, 2000; accepted May 23, 2000.
This work was supported by National Institutes of Health Grants
R29-MH58883 and S06-GM08236 to G.J.Q. We thank Mohammed Milad for
assistance with surgery and Justin A. Harris, Karim Nader, and
Francisco Olucha for comments on an earlier draft of this manuscript.
Correspondence should be addressed to Dr. Gregory J. Quirk, Department
of Physiology, Ponce School of Medicine, P.O. Box 7004, Ponce, Puerto
Rico 00732-7004. E-mail: gjquirk{at}yahoo.com.
| |
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Noradrenergic Signaling in Infralimbic Cortex Increases Cell Excitability and Strengthens Memory for Fear Extinction
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[Abstract]
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Y. S. Jo, E. H. Park, I. H. Kim, S. K. Park, H. Kim, H. T. Kim, and J.-S. Choi
The Medial Prefrontal Cortex Is Involved in Spatial Memory Retrieval under Partial-Cue Conditions
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J. M. Langton, J. H. Kim, J. Nicholas, and R. Richardson
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S. Hugues and R. Garcia
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E. L. Rich and M. L. Shapiro
Prelimbic/Infralimbic Inactivation Impairs Memory for Multiple Task Switches, But Not Flexible Selection of Familiar Tasks
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K. A. Corcoran and G. J. Quirk
Activity in Prelimbic Cortex Is Necessary for the Expression of Learned, But Not Innate, Fears
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January 24, 2007;
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C. L. Wellman, A. Izquierdo, J. E. Garrett, K. P. Martin, J. Carroll, R. Millstein, K.-P. Lesch, D. L. Murphy, and A. Holmes
Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice
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January 17, 2007;
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K. Zushida, M. Sakurai, K. Wada, and M. Sekiguchi
Facilitation of Extinction Learning for Contextual Fear Memory by PEPA: A Potentiator of AMPA Receptors
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J. Amat, E. Paul, C. Zarza, L. R. Watkins, and S. F. Maier
Previous Experience with Behavioral Control over Stress Blocks the Behavioral and Dorsal Raphe Nucleus Activating Effects of Later Uncontrollable Stress: Role of the Ventral Medial Prefrontal Cortex
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I. Vidal-Gonzalez, B. Vidal-Gonzalez, S. L. Rauch, and G. J. Quirk
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S.-C. Mao, Y.-H. Hsiao, and P.-W. Gean
Extinction Training in Conjunction with a Partial Agonist of the Glycine Site on the NMDA Receptor Erases Memory Trace.
J. Neurosci.,
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K. A. Burke, T. M. Franz, N. Gugsa, and G. Schoenbaum
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A. Izquierdo, C. L. Wellman, and A. Holmes
Brief Uncontrollable Stress Causes Dendritic Retraction in Infralimbic Cortex and Resistance to Fear Extinction in Mice
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May 24, 2006;
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T. V. Gurvits, L. J. Metzger, N. B. Lasko, P. A. Cannistraro, A. S. Tarhan, M. W. Gilbertson, S. P. Orr, A. M. Charbonneau, M. M. Wedig, and R. K. Pitman
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M. Farinelli, O. Deschaux, S. Hugues, A. Thevenet, and R. Garcia
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H.-C. Lin, S.-C. Mao, and P.-W. Gean
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K. M. Myers, K. J. Ressler, and M. Davis
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R. Garcia, C.-h. Chang, and S. Maren
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D. Anglada-Figueroa and G. J. Quirk
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E. Likhtik, J. G. Pelletier, R. Paz, and D. Pare
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R. Ponnusamy, H. A. Nissim, and M. Barad
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C. K. Cain, B. P. Godsil, S. Jami, and M. Barad
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L. M. Shin, C. I. Wright, P. A. Cannistraro, M. M. Wedig, K. McMullin, B. Martis, M. L. Macklin, N. B. Lasko, S. R. Cavanagh, T. S. Krangel, et al.
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S. Maren
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Neuroscientist,
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[Abstract]
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Z. Zhao and M. Davis
Fear-Potentiated Startle in Rats Is Mediated by Neurons in the Deep Layers of the Superior Colliculus/Deep Mesencephalic Nucleus of the Rostral Midbrain through the Glutamate Non-NMDA Receptors
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S. C. Azad, K. Monory, G. Marsicano, B. F. Cravatt, B. Lutz, W. Zieglgansberger, and G. Rammes
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K. Robleto, A. M. Poulos, and R. F. Thompson
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F. Sotres-Bayon, D. E.A. Bush, and J. E. LeDoux
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S. Hugues, O. Deschaux, and R. Garcia
Postextinction Infusion of a Mitogen-Activated Protein Kinase Inhibitor Into the Medial Prefrontal Cortex Impairs Memory of the Extinction of Conditioned Fear
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K. Lebron, M. R. Milad, and G. J. Quirk
Delayed Recall of Fear Extinction in Rats With Lesions of Ventral Medial Prefrontal Cortex
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S. E.V. Rhodes and S. Killcross
Lesions of Rat Infralimbic Cortex Enhance Recovery and Reinstatement of an Appetitive Pavlovian Response
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F. Gonzalez-Lima and A. K. Bruchey
Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue
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D. Pare, G. J. Quirk, and J. E. Ledoux
New Vistas on Amygdala Networks in Conditioned Fear
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D. S. Charney
Psychobiological Mechanisms of Resilience and Vulnerability: Implications for Successful Adaptation to Extreme Stress
Focus,
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S. Tronel, M. G.P. Feenstra, and S. J. Sara
Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation
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E. Santini, H. Ge, K. Ren, S. P. de Ortiz, and G. J. Quirk
Consolidation of Fear Extinction Requires Protein Synthesis in the Medial Prefrontal Cortex
J. Neurosci.,
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A. Suzuki, S. A. Josselyn, P. W. Frankland, S. Masushige, A. J. Silva, and S. Kida
Memory Reconsolidation and Extinction Have Distinct Temporal and Biochemical Signatures
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K. M. Lattal and T. Abel
Behavioral impairments caused by injections of the protein synthesis inhibitor anisomycin after contextual retrieval reverse with time
PNAS,
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[Abstract]
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G. J. Quirk
Learning Not to Fear, Faster
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D. S. Charney
Psychobiological Mechanisms of Resilience and Vulnerability: Implications for Successful Adaptation to Extreme Stress
Am J Psychiatry,
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L. M. Shin, S. P. Orr, M. A. Carson, S. L. Rauch, M. L. Macklin, N. B. Lasko, P. M. Peters, L. J. Metzger, D. D. Dougherty, P. A. Cannistraro, et al.
Regional Cerebral Blood Flow in the Amygdala and Medial Prefrontal Cortex During Traumatic Imagery in Male and Female Vietnam Veterans With PTSD
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J. A. Rosenkranz, H. Moore, and A. A. Grace
The Prefrontal Cortex Regulates Lateral Amygdala Neuronal Plasticity and Responses to Previously Conditioned Stimuli
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D. J. Krupa and R. F. Thompson
Inhibiting the Expression of a Classically Conditioned Behavior Prevents Its Extinction
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A. Ishikawa and S. Nakamura
Convergence and Interaction of Hippocampal and Amygdalar Projections within the Prefrontal Cortex in the Rat
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G. J. Quirk, E. Likhtik, J. G. Pelletier, and D. Pare
Stimulation of Medial Prefrontal Cortex Decreases the Responsiveness of Central Amygdala Output Neurons
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C.-H. Lin, S.-H. Yeh, H.-Y. Lu, and P.-W. Gean
The Similarities and Diversities of Signal Pathways Leading to Consolidation of Conditioning and Consolidation of Extinction of Fear Memory
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J. A. Hobin, K. A. Goosens, and S. Maren
Context-Dependent Neuronal Activity in the Lateral Amygdala Represents Fear Memories after Extinction
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S. Lissek and O. Gunturkun
Dissociation of Extinction and Behavioral Disinhibition: The Role of NMDA Receptors in the Pigeon Associative Forebrain during Extinction
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D. Barrett, J. Shumake, D. Jones, and F. Gonzalez-Lima
Metabolic Mapping of Mouse Brain Activity after Extinction of a Conditioned Emotional Response
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D. R. Catherall
How Fear Differs From Anxiety
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M. A. Pezze, T. Bast, and J. Feldon
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S. Killcross and E. Coutureau
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X. Ma and N. Suga
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C. K. Cain, A. M. Blouin, and M. Barad
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R. Adolphs
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TOP
ABSTRACT
INTRODUCTION
